Is EPAS1 p.Ser286= (c.858C>T) pathogenic?

EPAS1 p.Ser286= (c.858C>T) is classified Benign/Likely benign in EPAS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-08). Rare (popmax 0.106%, sas); Associated with Inborn genetic diseases.

What condition is associated with EPAS1 p.Ser286= (c.858C>T)?

EPAS1 p.Ser286= (c.858C>T) is associated with Inborn genetic diseases, erythrocytosis, familial, 4 (ClinVar).

How common is EPAS1 p.Ser286= (c.858C>T) in the general population?

EPAS1 p.Ser286= (c.858C>T) is rare (popmax 0.106%, sas) (gnomAD).

EPAS1 p.Ser286=

c.858C>T · rs567851666 · VCV336253

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.106%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -3.8
Overall
CADD	6.552	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.106% South Asian · 96/90,460 alleles

Filtering AF 0.0889% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0825%

Overall 0.00937% 151/1,611,988 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.106%	942
Admixed American	0.00836%	11,960
Remaining individualsnot grpmax-eligible	0.00801%	12,487
European (non-Finnish)	0.00373%	26,797
African / African-American	0.00133%	74,984

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EPAS1
Protein: p.Ser286=
Coding: c.858C>T
MANE Select: NM_001430
dbSNP: rs567851666
Type: single nucleotide variant
Location: chr2:46369905 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.41 · 43 PDB
Residue 286: the pas 2 domain; an α-helix

Full EPAS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: erythrocytosis, familial, 4

Similar variants

EPAS1 p.Gly537Arg Pathogenic ★★ ⚠ same condition
EPAS1 p.Met535Thr Pathogenic ★★ ⚠ same condition
EPAS1 c.-231C>G Uncertain significance ★★ same condition
EPAS1 p.Ala439Gly Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala463Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala698Pro Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala758Thr Uncertain significance ★★ ⚠ same condition
EPAS1 p.Ala81Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/epas1-p-ser286 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown